Before the introduction of modern vaccination programs, whooping cough, caused by the bacteria Bordetella pertussis, was the primary infectious cause of infant death. B. pertussis is highly specialized to its human host and produces a number of virulence factors, with no clear correlate of protection. Despite wide-spread, aggressive vaccination, pertussis not only persists but is increasing in incidence in the US and other industrialized countries. In 2012, more pertussis cases were reported in the US since 1955. Academic, pharmaceutical and regulatory members of the pertussis community agree on the need for a more immunogenic and efficacious pertussis vaccine, but how to achieve this is not clear. Therefore, advances in the scientific basis of pertussis pathogenesis and host protective mechanisms are needed. In particular, the adenylate cyclase toxin (ACT) is the leading candidate for inclusion in future vaccines, yet there is very little data detailing the mechanisms by which ACT confers protection or its appropriateness for manufacturing and formulation as a part of a multi-component vaccine. Here, we will perform the first systematic evaluation of ACT's role in protection. This work will involve a combination of in vitro biochemical and anti-bacterial assays as well as passive and active immunization experiments using a murine model of infection which is predictive of vaccine performance in humans. We aim to conclusively define the role of neutralizing and non-neutralizing anti-ACT antibodies in disease as well as to identify the immunological mechanisms and ACT epitopes necessary for protection.